1. Filed of the Invention
The present invention relates to a genetically immunodeficient nonhuman mammal with a human immune system. In particular, the present invention relates to a genetically immunodeficient mouse having human T-cells within its hematopoietic system, methods for producing these mice and methods for using this mouse model to assay for inhibitors of human immunodeficiency virus (HIV) infection and to assay substances for their effects on human T-cells.
2. Background Art
Progress in the development of drugs which alter immune system function or protect against retroviral infection have been impeded by the absence of a suitable in vivo model system of T-cell development. The requirement for the appropriate hematopoietic microenvironment complete with the requisite cytokines has in part been met by the SCID-hu mouse model system (Baum, C. M., et al. 1992. Proc. Natl. Acad. Sci. USA 89:2804-2808; McCune, J. M., et al. 1988. Science 241:1632-1639). SCID-hu mice contain grafts of fetal thymus, liver and bone marrow, which permit the development of human B-cells, T-cells and myeloid cells. Intraperitoneal injections of human peripheral blood have produced lymphoid engraftment in SCID mice although both the frequency and duration of engraftment have been low (Mosier, D. et al. 1988. Nature (London) 335:256-259). To circumvent these difficulties, SCID mice have been treated with injections of human progenitor cells and a cocktail of human cytokines. The use of exogenous cytokines in this setting modestly improves the frequency and extent of engraftment (Lapidot, T., et al. 1992. Science 255:1137-1140; Nolta, J. A., et al. 1994 Blood 83:3041). This finding is consistent with the observation that many murine growth factors are thought to have reduced activity on human progenitor cell populations. Human T-cells transplanted into immunodeficient mice have been demonstrated to be infectable with human immunodeficiency virus-1 (HIV-1) Namikawa, R., et al. 1988. Science 242:1684-1686; Mosier, D. E., et al. 1991. Science 251:791-794). The low percentage of human T-cells found in the peripheral blood, spleen and bone marrow of these recipient mice remains a major limitation to studying the effects of agents which may inhibit HIV-1 replication and infection. In summary, low levels of human T-cell engraftment and the absence of an unambiguous endpoint for evaluating the antiviral activity of specific agents significantly limits the utility of the current in vivo model systems for T-cell function. Thus, there remains a need for an in vivo model for human T-cell function in which greater levels of T-cell engraftment can be established for the purpose of developing reliable and reproducible assays to antiviral activity and the effects of various agents on human T-cell function.
The present invention satisfies this need by providing a genetically immunodeficient mammal having large numbers of T-cells of human origin in its hematopoietic system. The present invention also provides a method for generating these animal models and methods for using these animals in assays to screen for compounds with anti-HIV activity and to screen substances for their effects on human T-cells.